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      A century of exercise physiology: key concepts on coupling respiratory oxygen flow to muscle energy demand during exercise

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          Abstract

          After a short historical account, and a discussion of Hill and Meyerhof’s theory of the energetics of muscular exercise, we analyse steady-state rest and exercise as the condition wherein coupling of respiration to metabolism is most perfect. The quantitative relationships show that the homeostatic equilibrium, centred around arterial pH of 7.4 and arterial carbon dioxide partial pressure of 40 mmHg, is attained when the ratio of alveolar ventilation to carbon dioxide flow ( \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$${\dot{V}}_{A}/{\dot{V}}_{R}{CO}_{2}$$\end{document}

          ) is − 21.6. Several combinations, exploited during exercise, of pertinent respiratory variables are compatible with this equilibrium, allowing adjustment of oxygen flow to oxygen demand without its alteration. During exercise transients, the balance is broken, but the coupling of respiration to metabolism is preserved when, as during moderate exercise, the respiratory system responds faster than the metabolic pathways. At higher exercise intensities, early blood lactate accumulation suggests that the coupling of respiration to metabolism is transiently broken, to be re-established when, at steady state, blood lactate stabilizes at higher levels than resting. In the severe exercise domain, coupling cannot be re-established, so that anaerobic lactic metabolism also contributes to sustain energy demand, lactate concentration goes up and arterial pH falls continuously. The \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$${\dot{V}}_{A}/{\dot{V}}_{R}{CO}_{2}$$\end{document}
          decreases below − 21.6, because of ensuing hyperventilation, while lactate keeps being accumulated, so that exercise is rapidly interrupted. The most extreme rupture of the homeostatic equilibrium occurs during breath-holding, because oxygen flow from ambient air to mitochondria is interrupted. No coupling at all is possible between respiration and metabolism in this case.

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          The Science and Translation of Lactate Shuttle Theory

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            Piezos are pore-forming subunits of mechanically activated channels

            Mechanotransduction plays a crucial role in physiology. Biological processes including sensing touch and sound waves require yet unidentified cation channels that detect pressure. Mouse piezo1 (mpiezo1) and mpiezo2 induce mechanically activated cationic currents in cells; however, it is unknown if piezos are pore-forming ion channels or modulate ion channels. We show that Drosophila piezo (dpiezo) also induces mechanically activated currents in cells, but through channels with remarkably distinct pore properties including sensitivity to the pore blocker ruthenium red and single channel conductances. mpiezo1 assembles as a ~1.2 million-Dalton tetramer, with no evidence of other proteins in this complex. Finally, purified mpiezo1 reconstituted into asymmetric lipid bilayers and liposomes forms ruthenium red-sensitive ion channels. These data demonstrate that piezos are an evolutionarily conserved ion channel family involved in mechanotransduction.
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              Endothelial cation channel PIEZO1 controls blood pressure by mediating flow-induced ATP release.

              Arterial blood pressure is controlled by vasodilatory factors such as nitric oxide (NO) that are released from the endothelium under the influence of fluid shear stress exerted by flowing blood. Flow-induced endothelial release of ATP and subsequent activation of Gq/G11-coupled purinergic P2Y2 receptors have been shown to mediate fluid shear stress-induced stimulation of NO formation. However, the mechanism by which fluid shear stress initiates these processes is unclear. Here, we have shown that the endothelial mechanosensitive cation channel PIEZO1 is required for flow-induced ATP release and subsequent P2Y2/Gq/G11-mediated activation of downstream signaling that results in phosphorylation and activation of AKT and endothelial NOS. We also demonstrated that PIEZO1-dependent ATP release is mediated in part by pannexin channels. The PIEZO1 activator Yoda1 mimicked the effect of fluid shear stress on endothelial cells and induced vasorelaxation in a PIEZO1-dependent manner. Furthermore, mice with induced endothelium-specific PIEZO1 deficiency lost the ability to induce NO formation and vasodilation in response to flow and consequently developed hypertension. Together, our data demonstrate that PIEZO1 is required for the regulation of NO formation, vascular tone, and blood pressure.
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                Author and article information

                Contributors
                guido.ferretti@unibs.it
                Journal
                Eur J Appl Physiol
                Eur J Appl Physiol
                European Journal of Applied Physiology
                Springer Berlin Heidelberg (Berlin/Heidelberg )
                1439-6319
                1439-6327
                26 February 2022
                26 February 2022
                2022
                : 122
                : 6
                : 1317-1365
                Affiliations
                [1 ]GRID grid.7637.5, ISNI 0000000417571846, Dipartimento di Medicina Molecolare e Traslazionale, , Università di Brescia, ; Brescia, Italy
                [2 ]GRID grid.8591.5, ISNI 0000 0001 2322 4988, Département d’Anesthésiologie, Pharmacologie et Soins Intensifs, , Université de Genève, ; Genève, Switzerland
                [3 ]GRID grid.5390.f, ISNI 0000 0001 2113 062X, Professore Emerito di Fisiologia, , Università di Udine, ; Udine, Italy
                Author notes

                Communicated by Michael Lindinger.

                Author information
                http://orcid.org/0000-0001-7592-0416
                http://orcid.org/0000-0002-7312-8174
                http://orcid.org/0000-0002-8198-6574
                http://orcid.org/0000-0003-4743-532X
                Article
                4901
                10.1007/s00421-022-04901-x
                9132876
                35217911
                c18af14a-f9a8-4f6b-93e8-0b4827e4d58d
                © The Author(s) 2022

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 15 September 2021
                : 25 January 2022
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100001711, Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung;
                Award ID: 32003B_179448
                Award Recipient :
                Categories
                Invited Review
                Custom metadata
                © Springer-Verlag GmbH Germany, part of Springer Nature 2022

                Anatomy & Physiology
                oxygen flow,oxygen consumption,ventilation,diffusion,cardiac output,haemoglobin,metabolism,energetics,exercise transient,breath-holding

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